The most common cause of death due to falciparum malaria is cerebral malaria (CM). This occurs mainly among children. A serious impediment to progress in treating CM is the paucity of animal models for this syndrome. In rodents, P. berghei ANKA has been studied extensively as a model for CM. However, this model involves the participation of inflammatory cells which does not appear to be the case for humans. Recent studies from this laboratory indicate that P. yoelii 17XL (PyL) is a more appropriate rodent model for human CM than P. berghei ANKA. Therefore, we propose to characterize the P. yoelii 17XL model of CM and compare it to the non- lethal parent strain P.yoelii 17XNL. This will be accomplished by studying the histologic and electron microscopic change in the brains of different strains of mice infected with this parasite. In addition we will determine which brain endothelial molecules are elevated, and/or bind infected RBC and whether particular cytokines (TNFalpha, IFNgamma, IL1, & IL 10) or nitric oxide synthase (NOS) levels are elevated or depressed during CM in mice, using immunohistochemistry, measurement of mRNA and in situ hybridization. Based on the results, antibodies to, or inhibitors of the relevant molecules, as well as protein 3 peptides will be assayed for inhibition of cytoadherence in the in vivo mouse cremaster muscle preparation and in the rat mesocecum preparation, ex vivo. Successful treatments will be assayed in vivo, in mice infected with PyL, for reduction of CM. Finally, the role of sickle trait in CM will be determined using transgenic lines of mice that express beta/s hemoglobin infected with PyL and human sickle trait erythrocytes infected in culture with P. falciparum.